The present invention relates to a process for producing benzothiophenecarboxamide derivatives useful as prostaglandin D2 (hereinafter, referred to as xe2x80x9cPGD2xe2x80x9d) antagonists.
Benzothiphenecarboxamide derivatives of the general formula (I): 
wherein R is hydrogen or a hydroxy-protecting group, X is hydrogen or alkyl, and double bond represents E or Z configuration are PGD2 antagonists specific to PGD2 receptors and useful as therapeutic agents for treating diseases associated with the dysfunction of the mast cell caused by excessive production of PGD2 (WO97/00853, PCT/JP97/04527 (WO98/25919)). Consequently, the compound of the formula described above may be used as therapeutic agents for systemic mastocytosis, disorder of systemic mast cell activation, tracheal contraction, asthma, allergic rhinitis, allergic conjunctivitis, urticaria, injury due to ischemic reperfusion, inflammation, and atopic dermatis. Among them, a compound wherein OR is 5-hydroxy, X is hydrogen and double bond represents Z-configuration (hereinafter, referred to as xe2x80x9cCompound Axe2x80x9d) possesses high antagonistic effect on PGD2, showing especially high anti-nasal occlusion activity, and is contemplated to be a promising drug for treating nasal occlusion.
The compound (I) and processes for preparing the same have been known in literatures (WO97/00853, PCT/JP97/04527 (WO98/25919)). However, the known processes are not necessarily suited for industrial production in terms of production efficiency, safety for workers and environment and efficient use of resources because of the reasons exemplified as follows:
1) it uses silica gel chromatography unsuitable for mass production;
2) it is of low yield and time-consuming;
3) it involves complicated separation and purification processes of the reaction product;
4) it is accompanied by the generation of harmful gas, odor and/or waste fluid; and/or
5) it requires materials harmful or hard to handle as starting compounds, reagents, and/or solvents.
The present invention provides a process for preparing a compound of the formula (I): 
wherein R is hydrogen or a hydroxy-protecting group; X is hydrogen or alkyl; and double bond represents either E- or Z-configuration, or a pharmaceutically acceptable salt thereof or a hydrate thereof, which comprises reacting an amino alcohol of the formula (II): 
or a salt thereof with a compound of the formula (III): 
wherein R is hydrogen or a hydroxy-protecting group, or a reactive derivative thereof to yield a compound of the formula (I-2): 
wherein R is as defined above; oxidizing the compound (I-2) with halo oxoacid in the presence of a compound of 2,2,6,6-tetramethylpiperidine-1-oxyls to yield a compound of the formula (I-3): 
wherein R is as defined above; reacting the compound (I-3) with an ylide under the conditions for Wittig reaction and, if desired, deprotecting the reaction product.
In a preferred embodiment of the present invention, a compound of the formula (I-2): 
wherein R is as defined above is oxidized with halo oxoacid in the presence of 2,2,6,6-tetramethylpiperidine-1-oxyls to yield a compound of the formula (I-3): 
wherein R is as defined above.
In another preferred embodiment, a compound of the formula (II-2): 
wherein R2 is alkyl and R3 is hydrogen or alkyl is reduced with reducing agent-Lewis acid system to yield an amino alcohol of the formula (II) or a salt thereof.
Preferably, the reducing agent used is selected from the group consisting of alkaline metal- or alkaline earth metal-substituted borohydrides; and the Lewis acid is selected from the group consisting of halide of tin, aluminum, titanium, boron, zirconium or nickel and complexes thereof with ethers.
In another preferred embodiment, a compound of the formula (II-2): 
wherein R2 and R3 are as defined above is converted into an alcohol of the formula (II-3): 
wherein R3 is as defined above; and the alcohol is reduced with a reducing system of metal sodium-alcohol or reducing agent-Lewis acid to provide an amino alcohol of the formula (II) or a salt thereof.
The terms used herein are defined below.
The term xe2x80x9chydroxy-protecting groupxe2x80x9d means alkyl, alkoxyalkyl, acyl, aralkyl, alkylsulfonyl, arylsulfonyl, alkyl substituted silyl, alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl or tetrahydropyranyl.
The term xe2x80x9calkylxe2x80x9d means C1-C20 linear or branched alkyl, particularly, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, tridecyl, tetradecyl, pentadecyl, hexadecyl, heptadecyl, octadecyl, nonadecyl and icosyl, and C1-C6 alkyl is preferred. As alkyl for R2, C1-C3 alkyl is preferred.
The term xe2x80x9calkoxyxe2x80x9d means C1-C6 linear or branched alkoxy, particularly, methoxy, ethoxy, n-propoxy, i-propoxy, n-butoxy, i-butoxy, s-butoxy, t-butoxy, n-pentyloxy, i-pentyloxy, neopentyloxy, s-pentyloxy, t-pentyloxy, n-hexyloxy, neohexyloxy, i-hexyloxy, s-hexyloxy, t-hexyloxy and the like, and C1-C3 alkoxy is preferred.
The term xe2x80x9calkoxyalkylxe2x80x9d means alkyl group substituted by alkoxy group, including methoxymethyl, ethoxymethyl, methoxyethoxymethyl, ethoxyethyl, methoxypropyl and the like.
The term xe2x80x9cacylxe2x80x9d means C1-C11 acyl derived from aliphatic carboxylic acid or aromatic carboxylic acid. Examples of aliphatic carboxylic acid-derived acyl include acetyl, chloroacetyl, trichloroacetyl, propionyl, butyryl, valeryl and the like, and examples of aromatic carboxylic acid-derived acyl include benzoyl, p-nitrobenzoyl, p-methoxybenzoyl, p-bromobenzoyl, toluoyl, naphthoyl and the like.
The term xe2x80x9carylxe2x80x9d means phenyl, naphthyl or polycyclic aromatic hydrocarbon group and the like. In addition, aryl may be substituted by the following substituents.
Examples of substituent include alkyl such as methyl, ethyl, n-propyl, isopropyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, isopentyl, neopentyl or tert-pentyl, lower alkoxy such as methoxy or ethoxy, halogen such as fluoro, chloro, bromo or iodo, nitro, hydroxy, carboxy, cyano, sulfonyl, amino, lower alkylamino such as methylamino, dimethylamino, ethylmethylamino or diethylamino, and the like. The aryl group may have one or more substituents at any possible positions. Specific examples of aryl include 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-ethylphenyl, 4-pentylphenyl, 4-carboxyphenyl, 4-acetylphenyl, 4-(N,N-dimethylamino)phenyl, 4-nitrophenyl, 4-hydroxyphenyl, 4-methoxyphenyl, 4-fluorophenyl, 4-chlorophenyl, 4-iodophenyl and the like.
The aryl group in the xe2x80x9caralkylxe2x80x9d, xe2x80x9carylsulfonylxe2x80x9d, xe2x80x9caryloxycarbonylxe2x80x9d or xe2x80x9caralkyloxycarbonylxe2x80x9d described below may have similar substituents as defined above.
The term xe2x80x9caralkylxe2x80x9d means an alkyl group substituted by aryl group, and includes benzyl, 4-methylbenzyl, 4-methoxybenzyl, 3,4-dimethoxybenzyl, naphthylmethyl, phenethyl, and the like.
The term xe2x80x9calkylsulfonylxe2x80x9d means a sulfonyl group substituted by alkyl group, and includes methanesulfonyl, ethanesulfonyl and the like.
The term xe2x80x9carylsulfonylxe2x80x9d means a sulfonyl group substituted by aryl group, and includes benzenesulfonyl, p-toluenesulfonyl, and the like.
The term xe2x80x9calkyl-substituted silylxe2x80x9d means mono-, di- or tri-alkyl-substituted silyl, for example, methylsilyl, dimethylsilyl, trimethylsilyl, t-butyldimethylsilyl, and the like.
The term xe2x80x9calkoxycarbonylxe2x80x9d means methoxycarbonyl, isopropoxycarbonyl, t-butoxycarbonyl, and the like.
The term xe2x80x9caryloxycarbonylxe2x80x9d means phenoxycarbonyl, and the like.
The term xe2x80x9caralkyloxycarbonylxe2x80x9d means benzyloxycarbonyl, and the like.
As hydroxy-protecting group represented by R, the above-mentioned alkyl, alkoxyalkyl, acyl, aralkyl, alkylsulfonyl, arylsulfonyl, alkyl-substituted silyl, alkoxycarbonyl, aryloxycarbonyl, aralkyloxycarbonyl or tetrahydropyranyl are preferred and aryl sulfonyl is more preferred.
Examples of salts of a compound of the general formula (I) include alkali metal salts such as lithium salt, sodium salt or potassium salt and the like, alkali earth metal salts such as calcium salt and the like, ammonium salt, salts with organic base such as tromethamine, trimethylamine, triethylamine, 2-aminobutane, tert-butylamine, diisopropylethylamine, n-butylmethylamine, n-butyldimethylamine, tri-n-butylamine, cyclohexylamine, dicyclohexylamine, N-isopropylcyclohexylamine, furfurylamine, benzylamine, methylbenzylamine, dibenzylamine, N,N-dimethylbenzylamine, 2-chlorobenzylamine, 4-methoxybenzylamine, 1-naphthalenemethylamine, diphenylbenzylamine, triphenylamine, 1-naphthylamine, 1-aminoanthracene, 2-aminoanthracene, dehydroabiethylamine, N-methylmorpholine or pyridine, or amino acid salts such as lysine salt or arginine salt.
The salts of amino alcohols of the formula (II) include salts with organic acid such as benzoic acid, etc., and mineral acid such as hydrochloric acid, sulfuric acid, etc.
The objective compound of the present invention is illustrated by the general formula (I), in which the double bond of the alkenylene side chain (i.e., 5-heptenylene chain) may be in E- or Z-configuration.
The method of the present invention is described below in more detail. When a substituent(s) possibly interfering the reaction exists, it may be appropriately protected and deprotected at a desired stage. Such protection or deprotection can be accomplished by a procedure known in the art.

wherein R and X are as defined above.
[Step 1]
This step is related to the preparation of amide (I-2) by acylating an amino alcohol (II) or a salt thereof with carboxylic acid (III) or a reactive derivative thereof.
The carboxylic acid (compound III) used in the acylation can be synthesized by a method known in literatures [for example, Nippon-Kagaku Zasshi vol. 88, No. 7, 758-763 (1967); Nippon-Kagaku Zasshi vol. 86, No. 10, 1067-1072 (1965); J. Chem. Soc. (C). 1899-1905 (1967); J. Heterocycle. Chem. vol.10, 679-681 (1973)]. The term xe2x80x9creactive derivativexe2x80x9d of carboxylic acid (III) refers to corresponding acid halides (e.g., chloride, bromide, iodide), acid anhydrides (e.g., mixed acid anhydride with formic acid or acetic acid), activated esters (e.g., succinimide ester), and the like, and includes acylating agents generally used for the acylation of amino group. For example, to obtain acid halides, a carboxylic acid is reacted with thionyl halide (e.g., thionyl chloride), phosphorous halide (e.g., phosphorous trichloride, phosphorous pentachloride), oxalyl halide (e.g., oxalyl chloride), or the like, according to a known method (e.g., Shin-jikken Kagaku Koza, vol. 14, p. 1787 (1978); Synthesis 852-854 (1986); Shin-jikken Kagaku Koza vol. 22, p. 115 (1992)).
The acylation can be carried out under ordinary conditions used for the acylation of amino group. For example, when a carboxylic acid halide is used, the reaction is carried out according to a method commonly known as xe2x80x9cSchotten-Baumann reactionxe2x80x9d. In general, carboxylic acid halide is added dropwise to an aqueous alkaline solution of amine with stirring and under cooling while removing the generating acid with alkali. Alternatively, when a carboxylic acid is used as a free acid not a reactive derivative, the reaction can be conducted conventionally in the presence of a coupling agent generally used in the coupling reaction between an amine and a carboxylic acid such as dicyclohexylcarbodiimide (DCC), 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide or N,Nxe2x80x2-carbonyldiimidazole.
[Step 2]
This step is related to the oxidation of an alcohol (I-2) to an aldehyde (I-3). Hitherto such reaction has been conducted by using an oxidizing agent of chromic acid series such as Jones reagent (J. Org. Chem., 40, 1664-1665 (1975)), Collins reagent (J. C. S. Chem. Comm., 1972 1126) or pyridinium chlorochromate (Tetrahedron Lett., 2647-2650 (1975)). Further, methods wherein manganese dioxide (Helv. Chim. Acta., 39, 858-862 (1956)) or dimethyl sulfoxide (Swern oxidation, J. Org. Chem., 43, 2480-2482 (1978)) have been known. However, these existing methods have disadvantages. For example, chromic acids are toxic to human body and,must be detoxified after use. Further, the Swern oxidation using dimethyl sulfoxide-oxalyl chloride is not suited for a large scale production because it is accompanied by the generation of carbon monoxide harmful to workers and sulfurous odor and also it must be carried out at low temperature, for example, between xe2x88x9250xc2x0 C. and xe2x88x9278xc2x0 C.
According to the method of the present invention, alcohol (I-2) is oxidized with an oxidizing agent(s) such as halo oxoacid in the presence of 2,2,6,6-tetramethylpiperidine-1-oxyls (referred to as xe2x80x9cTEMPOsxe2x80x9d) as described in a literature (e.g., J. Org. Chem., 52, 2559-2562 (1987)), whereby the problems of existing methods are solved. Examples of TEMPO include 2,2,6,6-tetramethyl-piperidine-1-oxyl, 4-methoxy-2,2,6,6-tetramethylpiperidine-1-oxyl, 4-acetylamino-2,2,6,6-tetramethylpiperidine-1-oxyl, 4-benzoyloxy-2,2,6,6-tetramethylpiperidine-1-oxyl, and 4-cyano-2,2,6,6-tetramethylpiperidine-1-oxyl. Examples of halo oxoacid include sodium hypochlorite, sodium hypobromite, sodium bromite and higher bleaching powder. A solution of an oxidizing agent may be adjusted to, for example, pH 8.5 to 9.5 with a mineral acid such as sodium hydrogen carbonate, hydrochloric aci or sulfuric acid. Alternatively, a solution of an oxidizing agent may be added in the presence of sodium hydrogen carbonate. The reaction can be accomplished within several minutes to several tens minutes at temperature from ice-cooling to room temperature in a solvent such as ethyl acetate, acetonitrile or dichloromethane.
The advantageous characteristics of the new oxidation method of the present invention are as follows:
1) the process requires simple operations and short period of time since the reaction renders a product at high yield within short reaction time without keeping very lower temperature;
2) the process is safe since the reaction solvent used are water and ethyl acetate;
3) the separation and purification of reaction products can be conducted only by extraction;
4) the oxidation is carried out with a cheap reagent, sodium hypochlorite, with only a quite small amount of catalyst, TEMPO, at 1 0.2% molar equivalent to alcohol (I-2);
5) it allows the operators to work in better environment because the reaction generates little carbon monoxide or odor in contrast with Swern oxidation, and, further, sodium chloride resulting from sodium hypochlorite used in the oxidation is unnecessary to be detoxified.
[Step 3]
This step is related to the formation of a double bond by reacting a compound of the formula (I-3) with an ylide (Ph3P=CH(CH2)3COOH). The reaction for providing a double bond can be carried out in a conventional manner for Wittig reaction. The ylides used in the reaction can be synthesized, in the presence of a base, by treating a phosphonium salt which has been synthesized from triphenylphosphine and an alkyl halide having a desired alkyl group to be condensed, for example, 5-bromopentanoic acid. Examples of a base include dimsyl sodium, dimsyl potassium, sodium hydride, n-butyl lithium, potassium t-butoxide and lithium diisopropylamide. The reaction is accomplished within several hours at room temperature in a solvent such as ether, tetrahydrofuran, n-hexane, 1,2-dimethoxyethane or dimethyl sulfoxide.
[Step 4]
In this step, a compound (I) wherein R is hydroxy-protecting group is deprotected to provide compound (I-1). The reaction can be carried out in a conventional manner using, as a catalyst, hydrochloric acid, sulfuric acid, sodium hydroxide, potassium hydroxide or barium hydroxide, or the like. The reaction is accomplished within several tens minutes to several hours with heating in a solvent such as methanol-water, ethanol-water, acetone-water, acetonitrile-water, or the like, preferably dimethyl sulfoxide-water. The OR may be positioned at any of 4-, 5-, 6- and 7-positions though, it is preferred to be at 5-position.
The starting material in this process, amino alcohol (II), can be prepared by a known procedure starting from, for example, (xe2x88x92)-myrtenol. A precursor, methoxime ester of the formula (II-2) wherein R3 is methyl, is then reduced with metal sodium in isopropanol to give the corresponding amino alcohol (II) (Hagishita, et al., Chem. Pharm. Bull., 37(6), 1524-1533 (1989)). However, this method have problems such as low yield (39.6%) or poor selectivity.
As reducing agents used in the reduction of esters to alcohols, there have been known sodium borohydride (J. Org. Chem., 28, 3261 (1982)), lithium aluminum hydride (Org. Syn., 63, 140), lithium borohydride (J. Org. Chem., 47, 4702 (1982)) and the like. Further, as methods for reducing oximes to amines, there have been known catalytic reduction (Syn. Comm., 27, 817 (1997); Org. Syn., coll. vol. 5, 376 (1973)) or methods which use a reducing agent(s) such as diborane (J. Org. Chem., 30, 2877 (1965)), sodium borohydride (J. Org. Chem., 48, 3412 (1983)), lithium aluminum hydride (Tetrahedron, 51, 8363 (1995)), sodium borohydride-titanium chloride (IV) (Synthesis. 1980 695), sodium borohydride-nickel chloride (II) (Chem. Ber., 117, 856 (1984)), or the like. None of the literatures above, however, do not teach a method for reducing both ester and oxime moieties present in one molecule such as a compound of the formula (II-2) simultaneously in high yield with high stereoselectivity.
The present inventors have succeeded in reducing oxime ester of the formula (II-2) to the objective amino alcohol (II) in high yield with high selectivity by using a reducing agent-Lewis acid system (especially, sodium borohydride-Lewis acid) as shown in Scheme II below. 
wherein R2 and R3 are as defined above.
According to the present process, an oxime ester (II-2) is reduced directly or via alcohol (II-3) to give an amino alcohol (II) or a salt thereof. Reducing agents usable in the reaction above include alkali metal- or alkaline earth metal-substituted borohydrides (sodium borohydride, lithium borohydride, calcium borohydride, etc.).
Examples of Lewis acid include halides of tin, aluminium, boron, titanium, zirconium or nickel (e.g., stannous chloride, stannic chloride, aluminium chloride, titanium tetrachloride, boron trifluoride, zirconium tetrachloride, nickel dichloride, etc.) or a ether complexes thereof (e.g., sodium bis(2-methoxyethoxy)aluminium hydride, etc.).
Examples of solvent include ethers (e.g., ethyl ether, tetrahydrofuran, 1,2-dimetoxyethane, dioxane, diethylene glycol dimethyl ether, etc.), hydrocarbons (e.g., toluene, xylene, etc.), and a mixed solvents between ethers and hydrocarbons. Regarding the reduction of an alcohol (II-3) to an amino alcohol (II) or its salt, a method which uses metal sodium-alcohol is also availabe in addition to the above-mentioned reducing agent-Lewis acid system. Examples of alcohol include methanol, ethanol, n-propanol, i-propanol, and the like. Examples of solvents include hydrocarbons (e.g., toluene, xylene, etc.)
The process for reaction will be described concretely below. The raw material, oxime ester (or alkyl-substituted oxime) (II-2a or II-2b) is dissolved in 2 volumes or more of a solvent. To the solution are added 2 or more molar equivalents of a reducing agent and then a Lewis acid at 0.1 to 0.4 molar equivalents to the reducing agent at 0xc2x0 C. to 150xc2x0 C. Alternatively, a mixture previously prepared by combining a Lewis acid and a solvent may be added. Further, the order for adding a raw material, an oxime ester, a reducing agent and a Lewis acid can be changed. The reaction mixture is then treated at 0xc2x0 C. to 150xc2x0 C. for several minutes to several hours for reaction. The reaction solution can be worked up by adding water and dilute mineral acid (e.g., dilute hydrochloric acid) followed by stirring, whereby the reducing agent is destroyed. Alternatively, the reaction solution may be poured into dilute mineral acid.
The solution is then neutralized with an alkali (e.g., sodium hydroxide) and extracted with an organic solvent (e.g., ethyl acetate). When the solvent is distilled off, an amino alcohol (II) is obtained. If necessary, the product can be further purified by converting into a crystalline salt (IIxe2x80x2) with an appropriate acid (e.g., benzoic acid) and then neutralizing with an alkali to give amino alcohol (II).
According to the above-mentioned process of the present invention, the objective amino alcohol (II) can be prepared in high yield (about 89%) with high stereoselectivity (99% or more).
Although the process for preparing a compound of the formula (II) shown in the scheme II above is novel and useful for the preparation of a compound (II) in itself, it also contributes to establish safe and efficient production of a compound (I), the final product, when combined with a process for preparing the compound (I).